Therapeutic preparations for topical application to the skin



Z,9l,399 Patented Aug. 25, 1959 lice THERAPEUTIQ PREPARATIONS FORTOPICAL APPLICATION TO THE SKIN No Drawing. Application May 20, 1955Serial No. 510,029

20 Claims. Cl. 16787) This invention pertains to therapeuticcompositions and more particularly to compositions for the treatment ofdermatological disorders of the scalp and other epithelial areas of thebody.

The scalp condition commonly referred to as dandruff and medically knownby the generic term pityriasis is of general occurrence and is found inseveral forms and many degrees of severity. Despite widespread interestin the nature and causes of dandruff extending over many years in thepast, there is still no agreement among dermatologists as to the numberor importance of the causative factors.

A prevalent theory is that this condition is the result of a. normalphysiological process, i.e., the flaking of the superficial areas ofdead epithelial tissue. It is known that the cells over the entireepidermal surface of the human body continuously die and, in the processof replacement by the regeneration of new tissue, are sloughed off.Generally such dead tissue is removed, unnoticed by the individual, inthe normal course of daily activities, as by bathing or the slightabrading action of the clothing. However, in the case of the scalp, lossof such dead tissue is prevented by mixture with the oily secretions ofthe skin and retention by the hair. According to this theory, observeddifferences in the quantity and appearance of dandruff in differentindividuals is due only to the differences in the normal physiologicalprocesses of those individuals.

Another common theory is that pityriasis or dandruff is caused by one ormore microbiological organisms of a pathogenic or saprophytic nature.Despite the fact that an appreciable microbiological flora is associatedwith the normal human scalp, investigations have revealed that manyabnormal scalp conditions, with or without visible scalp irritation orlesions, are accompanied by an increase in the numbers of one or moretypes of organisms .as determined by standard microbiological culturetechniques. Against this theory is the inability up to the present timeto transfer from one individual to another,

.by known culture methods, the disorders loosely grouped under the termdandruff. Thus, although certain clinically identifiable scalp disordersare generally accompanied "by the presence of greater or lesser numbersof a particular organism or group of organisms, the importance of ,thisfactor is not well known. cause of the lack of a better standard, manyinvestigators have used the microbiological culture technique asNevertheless, in part be pityriasis capitis, and seborrheic dermatitis.Commonly present in association with one or more of the foregoingdiseases are the following organisms: certain species of ,the genusMucor, certain species of the genus Aspergillus, certain of theyeast-like fungi such as Monolia and Torula, Pityrosporum ovale,Bacillus substilis, Staphylococcus aureus and Staphylococcus albus.

Despite the lack of understanding of the cause of dandruff and similarscalp conditions, there have been in the past many attempts attreatment. Among the active ingredients which have been or are currentlybeing utilized in therapeutic compositions of the prior art areelemental sulphur in a variety of forms as well as chemically combinedsulphur in the form of polythionic acids, polythionates and certainsulfanilamide derivatives. Selenium compounds, such as selenium sulfide,have also appeared in prior art compositions of this general nature.

These prior attempts to control dermatological disorders of theaforementioned and similar types have, in general, proven unsatisfactoryin one or more respects. Thus, compositions containing free sulphur havea disagreeable odor whereas selenium compounds are highly toxic andconsequently must be used with extreme caution, as by incorporation intoa shampoo which is removed shortly after application. Many compounds ofthe sulfanilamide type result in a sensitizing action thereby limitingtheir usefulness as therapeutic agents. Further, the prior arttherapeutic compositions for treatment of the scalp generally possesspoor hair grooming qualities. Even where one or more of thesedisadvantages have been partially overcome by the prior art, it oftenhas been found that the condition under treatment was not amenable tosuch therapy or that the therapeutic agents were ineffective toappreciably reduce the severity of the condition except by frequent andextended application.

Therefore, a primary object of the present invention is to provide, forthe effective treatment of disorders of the scalp and other epithelialareas, a therapeutic composition which does not have the objectionablefeatures of prior art compositions.

Another object is to provide a therapeutic composition which is usefulto cleanse the hair and scalp.

Another object is to provide a therapeutic scalp cleanser which may besafely used without supervision by a physician and which is compatiblewith soaps, detergents, hair dyes, hair grooming agents, wave setpreparations and the like.

A still further object of the invention is to provide a therapeuticsalve or ointment for the treatment of seborrheic conditions of theskin.

Yet another object is to provide a method for successful treatment ofdandruff and related skin diseases.

Other objects and advantages of this invention will be come apparentfrom an inspection of the following detailed description.

It is known that certain compounds containing the thionate radical, S,,Opossess a bactericidal and fungicidal action and are useful in thetreatment of skin diseases when applied topically. Thus, Neesby, inUnited States Reissue Patent No. 23,711, discloses Polythionic acids andalkali metal salts thereof having the formulae R S O wherein R is analkali metal cation and n is an integer from 4 to 6. Such compounds,i.e., the tetra-, pentaand/or hexathionic acids or thionates exert aphysiological sulphur action but do not possess the many disadvantagesinherent in elemental sulphur. They are water soluble and, in the formof aqueous solutions, are useful in the topical treatment of skindiseases.

The polythionic acids and polythionates, such as described by Neesby,are, however, insoluble in compositions having high alcohol contents. Itis known that many hair grooming agents contain, as an essentialingredient thereof, a large percentage of alcohol. The present inventioncontemplates such a hair grooming composition which is also effective asa therapeutic scalp composition in part by reason of the incorporationtherein of an alcohol-soluble derivative of any one of a number of or amixture of polythionic acids or polythionates.

The alkali metal salts of polythionic acids may be chemically combinedwith halogenated amines to yield alcohol-soluble amine salts. Forexample, the "products of the reaction between alkali metalpolythionates and halogenated primary, secondary and tertiary amines arecontemplated. As products of such contemplated reactions, there may bementioned tetradecylamine polythionat'es, the 2, 2', diethyldihexylaminesalt ofv .polythionic acids and the dime'thyloctadecylamine saltofpolythionic acids. Illustrative of such compounds is'the reactionproduct of the sodium salts of a mixture of polythionates such asdescribed by Neesby and a'quaternary ammonium halide. Thus where n is aninteger from 4 to 6, X represents a halogen, and R represents an alkylgroup having from 1 to 24 and preferably from 12 to 18 carbon atoms, anarfylgroup, a hydroaryl (cycloaliphatic) group, an aral'kyl :groupor analkyl 'hydroaryl group wherein the alkyl moiety, in each instance, hasfrom 1 to 3 carbon atoms, or any combinations thereof.

The products of such reactions can be Written, in a more specific form,as

where R represents an alkyl group having from 1 to :10 carbon atoms,andR is the same as in the general formula in Equation I, except thatthe. alkyl group contains preferably from 6 to 24 carbon atoms. I Itshould be noted'that in any particular compound, it is not necessarythat all groups denoted by R or R have the same structure. Anycombination of the specified structures is suitable. V V p 1Illustrative of products which may result from reactions of this typeare:

Phenyltrimethylammonium polythionate Phenylethyltrimethylammoniuinpolythionate out-0H Ethylcyclohexyltrimethylammonium polythionate Apreferred reaction is that between a mixture of sodisum .polythionatesand dodecylthrimethylammonium chlo- The product of the above reaction,dodec'yltrimethylammonium polythionate, is highly alcohol-soluble.

Quaternary ammonium polythionates, such as dodecyltrimethylammoniumpolythionates, 'utilizable for the purposes of the present invention areavailable commercially in the form of a viscous, syrupy mass having anacidic reaction and containing a maximum of about 10% by weight-of Waterand -about'32' to 35% by-Weight of total icily'thior'iate. I v It hasnow been discovered that skin diseases such as those previouslydescribed, are surprisingly responsive to theabove-describedalcohol-soluble 'poly'thio'nate salts when topicallyapplied in conjunction with an amine salt of certain acyla-ted'amin'oacids-or alkyl N-substituted derivatives thereof. The amino acidderivatives contemplated'by'this invehtion'inayhavecompositionsasindicateab ene o'f-the'following formulae:

0 R R'i J-l I(OH2);ti J--OH-N(R) (VIII) wherein:

R. rep'1'e'sfents, ahjilkylgroup "having from 6 to 24 and Iprererablyffrgmlzto l8 carbon atoms; v R represents H or'an'a'lk'ylgroup "having from ltoS "carbonfatom's; M R". represents analkyl'jgr'oup having-from '1 to 24 ".and'p'refiably from '1'2'to '18carbon'at'oms, 'an aryl group, ahydroalryl; commonlyknown ascycloaliphatic, group, aralkyl 'g'roup,'oran alkyl hydroaryl groupwhere'iu'fthe alkylportion, in each instance, has from 1 to3:carbon"ato1ns,'or any combination thereof, and n is an integer 1 or 2;

0 0 n a 7g RC- N-CHQ 0H -N(R) (IX) wherein R, :R' and R7representthesarne respective groups as in Formula VIII above, andtheportion of the formula within. the brackets may be replaced by anyother amino acid moiety.

:As examples of compounds having formulae according to VIII or 1X,above, the following may be mentioned:

The dimethyl. salt of 'palmitoyl glycine,

p v o on"J 'GH;;( @5 2) 0H The ,cyclohexylamine -salt-ofl palmitoylsarcosine,

"Thefl-ph'enylethyl amine salt-of palmi'toyl fr-alanine,

*Component d The fi-cyclohexylethylamine salt of palmitoyl p-alanine,

(XIII) Illustrative of a preferred class of amino acid derivatives arealiphatic amine salts of N-lauroyl sarcosinate CH OH H H (X V) Compoundssuch as the above are highly soluble in ethyl alcohol.

A preferred composition containing both of the above types of compoundsas active or therapeutic ingredients may be illustrated by the followingexample.

EXAMPLE 1 Liquid formulation Weight percent Dodecyltrimethylammoniumpolythionate 3 Tetradecylammonium lauroyl sarcosinate 0.5 Ethyl alcohol(95 75 Water 21.5

Because of the insolubility of the therapeutic agents in water, it isnecessary, in order to obtain their complete solution, to have a minimumalcohol content of about 65%. The solvent phase of the therapeuticcomposition may comprise as much as 100% of 95% alcohol.

The concentrations of the active ingredients, for example,dodecyltrimethylammonium polythionate and tetradecylammonium lauroylsarcosinate as in Example 1, above, may be increased if desired to thelimits of their respective solubilities which are known to be higherthan those specified in Example 1.

There may be added to the above compositions varying amounts of waterandalcohol-soluble grooming agents such as a butyl ether of polypropyleneglycol or vegetable oils such as castor oil. The total amount of suchingredients may comprise from 0 to about 20% of the total composition.An acceptable hair grooming product has been found to be one having thecomposition of Example 1 above except that the water content isdecreased to 16.5% and 5% of Ucon (a butyl ether of polypropylene glycolis added). Preferably the pH of the composition is adjusted toapproximate that of the scalp.

In the process of manufacture of the liquid therapeutic compositions ofthis invention, the two therapeutic components, together with a groomingmaterial and a perfume (if included), are dissolved in the alcohol. Thewater (if included) is then added and the pH is adjusted by the additionof a suitable acid or base. Finally, the product is clarified byfiltration.

' The polythionate salts and the amino acid derivatives contemplated bythis invention may also be utilized in compositions wherein the solventphase is comprised wholly or partially of solvents other than ethylalcohol or ethyl alcohol-water mixtures. Such other solvents must alsobe non-toxic, non-sensitizing, non-irritant, compatible with soaps,detergents, etc., and are exemplified by isopropyl alcohol, certainglycols, such as dipropylene glycol, propylene glycol, polypropyleneglycol 200, certain polyethylene glycol esters, such as polyethyleneglycol 400 monolaurate or certain sorbitol derivatives of polyethyleneglycol such as Atlas Powder Company product G-2004.

The therapeutic ingredients contemplated by the present invention mayalso be incorporated into a salve or ointment for topical application inthe treatment of skin diseases. Such an ointment may comprise anemulsion having water as the principal component of the con tinuousphase and including, as the disperse phase, a suitable inert oiltogether with the therapeutic components. Suitable emulsifiers,preservatives, diluents, humectants, etc., may be added as desired. Thefollowing example is illustrative of a preferred ointment composition.

In Example 2, stearic acid and petrolatum, together with thetherapeutically active ingredients, i.e., tetradecylammonium lauroylsarcosinate and dodecyltrimethylammonium polythionate, constitute thedisperse phase of the emulsion and water as the principal component ofthe continuous phase. Propylene glycol serves as an humectant and thebenzoates are preservatives.

In compounding a formulation as in Example 2, the water, propyleneglycol and methyl p-hydroxy benzoate are mixed and heated to about C.The remaining ingredients are mixed in another batch and heated to thesame temperature whereby the solid or semi-solid components are meltedand the therapeutic agents, being oil-soluble to an extent, aredissolved or suspended therein. The separate batches are then mixed,with agitation, and allowed to cool.

Ointment formulations of the general character of Example 2 may containup to a total of about 30% of the therapeutic ingredients. Varioussubstitutions and additions may be made in the case of thenon-therapeutic components.

Both the polythionate derivatives and the amino acid derivativescontemplated by the present invention possess, to a slight extent,bactericidal and fungicidal properties. However, cultures ofmicrobiological organisms obtained from scalps exhibiting clinicalsymptoms of the abnormal conditions under consideration herein haveshown that the use of the compositions of this invention, wherein thepolythionate derivatives and the amino acid derivatives are combined,result in a marked decrease of the numbers of one or more types oforganisms associated with these abnormal conditions.

Likewise, neither the use of either component alone nor thenon-concurrent use of both components on the same individual results inmarked or unexpected effectiveness with respect to dandruff. However,when these two therapeutic agents are applied in conjunction with one,another the result is truly remarkable. Thus, laboratory studies carriedout in the course of the present in vestigation, haveshown thatthe'amino acidderivative, when topically applied inan alcohol-containingsolvent,

'hasvery little eifect on scalp "dandrufl similarguse of thepolythioriate derivative alonedoes reduce dandrutli, though not to'nearlyso great an extent as does-"the use of the combination of thesetwo ingredients in the compositions of the present invention.

Clinical tests have been carried out on human sub jects exhibiting alldegrees of" severityof dandruff and similar disorders. Such tests" haveutiiized the polythionate component alone, the amino acid derivativealone, and the combination of the two, in each case the activeingredient or ingredients being dissolved in a solvent comprising eitheralcohol alone or alcohol plus water. Each individual was treated(non-concurrently) with each of these three compositions. The resultswere quite strik- 7 ing. Thus, by way of illustration, in cases ofsevere pityriasis of the scalp which'had proven non-responsive to anyother therapeutic agent, the separate use of the polythionate solutionand the amine solution resulted in from two to four days relief fromscaling. On the other hand, application of the combinedpolythionate-amino acid derivative solution resulted in a three weeksremission of all dandruff. This procedure has been tried on differentsubjects, always with similar results. Diagnoses of skin conditionsofthese subjects varied from pityriasis sicca and oleosa to seborrheicdermatitis associated with pityriasis. These results show that there ispresent a pronounced synergism when the two therapeutic agents arecombined,

Additional tests of the combination product have conclusively shown itseffectiveness in the rapid and prolongedcontrol of dandruff and relateddisorders as well as its very appreciable superiority over any otherknown therapeutic. composition used for the same purpose.

The compositions contemplated by the present invention are extremelysafe in use. No sensitization or irritation of normal or abraded skinwas observable during the course of safety tests of these compositions.This is a decided advantage overmany prior art compositions.

Furthermore, the therapeutic compositions of the present inventionexhibit no deleterious effect on the hair.

There is no embrittlement, undue softening or discoloration such asresults from the use of many of the compositions of the prior art. Thecompositions of the present invention are compatible with commerciallyavailable soaps, detergents, shampoos, hair dyes, hair grooming agents,wave set preparations and the like. They do not exhibit theobjectionable odors so commonly associated with many prior artpreparations.

The liquid preparations of the present invention may be applied to thehair and scalp without unduly interfering with the normal activity ofthe individual. Thus, the therapeutic scalp preparation contemplated bythe present invention may be applied beforewashing the hair or it may beapplied at any time and allowed to remain on the hair for prolongedperiods. The latter procedure is particularly desirable when a separategrooming agent has been added.

The mild detergent action of the amino acid derivatives contemplated bythis invention lends to these therapeutic compositions the properties ofself-shampoos, although the foaming action is not markedly pronounced.Formulations may be made for use as shampoos wherein ordinary types ofsoaps or detergents are added to produce more thorough dirtandoil-removing action. If the slight foaming action of my compositions isundesirable, this action may be modified by the addition of a siliconefoam inhibitor of a type having the general formula i -o-s1- It. is tobe understood that the specific illustrations,

where n represents an integer 1 to 2, R is selected from the group.consisting of alkyl radicals having from 6 0 24 carbon atoms, R isselected from the group consisting of H and, an 'alkyl radical havingfrom '1 to 5 carbon atoms. and R is selected from the group consistingof H, an alkyl radical having from 1 to 24 carbon atoms, aryl radical, ahydroaryl radical, an aralkyl radicaLflan alkyl hydroaryl radical andcombinations thereof, wherein the alkyl moiety in said aralkyl radicaland said alkyl hydroaryl radical contains from 1 to 3 carbon atoms,

and a compound having the formula where n represents an integer from 4to 6, and R is an alkyl radical having from 1 to 24 carbon atoms.

2. A therapeutic composition for the treatment of diseases of the skincomprising an amine salt of an 'acylated amino acid selected from thegroup consisting of glycine, alanine, beta-alanine and sarcosine whereinthe acyl portion of the molecule contains an aliphatic group having from6 to 24 carbon atoms, a mixture of alkyl amine salts of polythionicacids having the formula H S O where n is an integer from 4 to 6, and asolvent for all,

of said salts.

3. A therapeutic composition for the treatment of skin diseasescomprising an aliphatic amine salt of a aCyla-ted derivative ofsarcosine wherein the acyl portion of said salt contains an aliphaticgroup having from 6 to '24 carbon atoms and each substituent of thealiphatic amine portion of the molecule contains from 1 to 24 carbonatoms, quaternary ammonium polythionates having the where n is aninteger from 4 to 6 and R is an alkyl group having from 6 to 24 carbonatoms, and a solvent for said salt and said poly-thionates.

4. A therapeutic composition for the treatment of dis cases of the skincomprising an aliphatic amine salt of N-lauroyl sarcosinate, quaternnaryammonium polythionates having the formula where n is an integer from 4to 6 and R is an alkyl group having from 6 to 24 carbon atoms, and asolvent for said salt and said polythionates.

5. A synergistic composition for the therapeutic treatment of skindiseases comprising tetradecylamine lauroyl sarcosinate anddodecyltrimethylammonium polythiomates.

6. A therapeutic composition for the treatment of diseases comprisingtetradecylamine lauroyl sarcosinate, dodecyltrimethylammoniumpolythionates, and a solvent. 7. A therapeutic composition for thetreatment of skin diseases comprising tetradecylamine lauroylsarcosinate, do ecy y ium p y ion es, and. an al ohol containin'gsolvent.

8. A therapeutic ointment for the treatment of skin diseases comprisingtetradecylammonium lauroyl sarcosinate, dodecyltrimethylammoniumpolythionates, and an inert vehicle for said sarcosinate and saidpolythionates.

9. A therapeutic ointment for the treatment of skin diseases comprisingan aliphatic amine salt of an amino acid amide, aliphatic amine salts ofa mixture of tetra-, penta-, and hexathionic acids, and a suitablevehicle therefor.

10. An emulsion having therapeutic properties and comprising acontinuous phase consisting substantially of water, and a disperse phaseincluding an inert oil, an amine salt of an amino acid amide and anamine salt of a polythionic acid.

11. A therapeutic emulsion comprising a continuous phase consistingsubstantially of water, and a disperse phase including petrolatum,tetradecylammonium lauroyl sarcosinate and dodecyltrimethylammoniumpolythionate.

12. A combined therapeutic and hair grooming composition comprising asolute including tetradecylamine lauroyl sarcosinate,dodecyltrimethylammonium polythionates, a butyl ether of polypropyleneglycol, and a solvent for said solute.

13. A therapeutic composition for the treatment of skin diseasescomprising an amine salt of a compound selected from the groupconsisting of acylated amino acids and alkyl N-substituted derivativesthereof wherein the acyl portion of said compound contains an aliphaticgrOup having from 6 to 24 carbon atoms, said amino acid is selected fromthe group consisting of glycine, alanine, beta-alanine and sarcosine andthe alkyl substitueut of said amino acid derivative contains from 1 tocarbon atoms, a quaternary ammonium polythionate having the where nrepresents an integer from 4 to 6, R is an alkyl radical having from 1to 24 carbon atoms, and a solvent for said salt and said polythionate.

14. A therapeutic composition for the treatment of skin diseasescomprising an amine salt of a compound selected from the groupconsisting of acylated amino acids and alkyl N-substituted derivativesthereof wherein the acyl portion of said compound contains an aliphaticgroup having from 6 to 24 carbon atoms, said amino acid is selected fromthe group consisting of glycine, alanine, beta-alanine and sarcosine andthe alkyl substituent of said amino acid derivative contains from 1 to 5carbon atoms, a quaternary ammonium polythionate having the where nrepresents an integer from 4 to 6, R is an alkyl radical having from 6to 24 carbon atoms and R is an alkyl radical having from 1 to 10 carbonatoms, and a solvent for said salt and said polythionate.

15. The composition of claim 14 wherein R represents the methyl group,CH

16. The composition of claim 15 wherein R is an alkyl group having from12 to 18 carbon atoms.

17. A therapeutic composition for the treatment of skin diseasescomprising an aliphatic amine salt of a compounds selected from thegroup consisting of an acylated amino acid and alkyl N-substitutedderivatives thereof wherein the acyl portion of said compound containsan aliphatic group having from 6 to 24 carbon atoms, said amino acid isselected from the group consisting of glycine, alanine, betaalanine andsarcosine and the alkyl substitueut of said amino acid derivativecontains from 1 to 5 carbon atoms, dodecyltrimethyl ammoniumpolythionates, and a solvent for said salt and said polythionates.

18. A therapeutic composition for the treatment of skin diseasescomprising an amine salt of an acylated derivative of sarcosine whereinthe acyl portion of said derivative contains an aliphatic group havingfrom 6 to 24 carbon atoms, a quaternary ammonium polythionate, and asolvent for said salt and said polythionate.

19. A therapeutic composition for the treatment of skin diseasescomprising an aliphatic amine salt of an acylated derivative ofsarcosine wherein the acyl portion of said derivative contains analiphatic group having from 6 to 24 carbon atoms, dodecyltrimethyl ammonitun polythiouates, and an alcoholic solvent for said salt and saidpolythionates.

20. A therapeutic composition for the treatment of skin diseasescomprising an amine salt of a compound selected from the groupconsisting of an acylated amino acid and alkyl N-substituted derivativesthereof wherein the acyl portion of said compound contains an aliphaticgroup having from 6 to 24 carbon atoms, said amino acid is selected fromthe group consisting of glycine, alanine, beta-alanine and sarcosine andthe alkyl substituent of said amino acid derivative contains from 1 to 5carbon atoms, an alkyl amine salt of a polythionic acid wherein eachalkyl substitueut of said polythionic acid salt contains from 1 to 24carbon atoms, and a solvent for said salts.

References Cited in the file of this patent UNITED STATES PATENTS2,689,170 King Sept. 14, 1954 FOREIGN PATENTS 60,457 Netherlands Jan.15, 1948 632,929 Great Britain Dec. 5, 1949 635,522 Germany Sept. 18,1936 745,340 Germany Mar. 16, 1944 OTHER REFERENCES Lesser: D. and Cos.Ind, March 1952, vol. 70, No. 3, pp. 320, 422.

J.A.M.A., vol. 139, No. 13, Mar. 26, 1949, pp. 840- 844. V

1. A SYNERGISTIC THERAPEUTIC COMPOSITION FOR THE TREATMENT OF SKINDISEASES COMPRISING A COMPOUND HAVING THE FORMULA